Cell type-specific functions of HMGB1 in necroinflammation of the kidney

前期研究结果表明，细胞外组蛋白和中性粒细胞细胞外陷阱在急性缺血后肾损伤的肾脏炎症坏死中起重要作用。但无法研究细胞类型特异性的细胞外组蛋白来源，因为细胞类型特异性的组蛋白耗尽在技术上是不可行的。因此，我们在这里集中在核蛋白高迁移率族蛋白盒（Hmgb）-1，它在细胞外空间中发挥类似于组蛋白的DAMP作用。由于Hmgb 1在细胞核中是可分散的，因此Hmgb 1-flox小鼠已经成为可用的。我们将产生在肾小管上皮细胞、常驻免疫细胞和浸润免疫细胞中选择性耗尽Hmgb 1的小鼠品系。诱导缺血后肾小管坏死伴急性肾损伤后，可以研究来自每种细胞类型的Hmgb 1的贡献。有必要区分Hmgb 1的细胞内和细胞外功能。基于我们的初步工作，该项目将特别关注急性肾损伤的长期结果，即肾再生和肿瘤发生，这两者在急性肾损伤后密切相关。我们将研究Hmgb 1的药理学抑制以及Hmgb 1的细胞类型特异性缺陷对这些结果的影响。我们期望对急性肾损伤后肾坏死性炎症及其对长期预后的影响有更好的了解。

The rsults of the previous project document that extracellular histones and neutrophil extracellular traps have important roles in renal necroinflammaiton of acute postischemic kidney injury. But the cell type-specific sources of extracellular histones could not be studied, because cell type-specific depletion of histones is technically not feasible. Therefore, we focus here on the nucleoprotein high mobility group box (Hmgb)-1, which elicits similar DAMP effects as histones in the extracellular space. Because Hmgb1 is dispensible in the nucleus Hmgb1-flox mice have become available. We will generate mouse lines with selective depletion of Hmgb1 in tubular epithelial cells, resident immune cells, and infiltrating immune cells. After induction of a postischemic tubular necrosis with acute kidney injury the contribution of Hmgb1 from each cell type can be studied. It will be necessary to distingiush intracellular from extracellular functions of Hmgb1. Based on our preliminary work this project will focus in particular on the long-term outcomes of acute kidney injury, i.e. kidney regeneration and tumorigenesis, which are both tightly connected after acute kidney injury. We will study the effects of pharmacological inhibition of Hmgb1 as well as the cell type-specific deficiency of Hmgb1 on these outcomes. We expect a bette runderstanding of renal necroinflammation and its impact on the long-term outcomes after acute kidney injury.